Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells

Adenosine concentrations in solid tumors are elevated as a result of altered metabolism by hypoxic cancer cells within the tumor microenvironment. In this study we show that adenosine inhibits mouse natural killer (NK) cell function by interfering with the process of granule exocytosis. Adenosine, at concentrations ranging from 5-25 μM, had a marked inhibitory effect on granule exocytosis by mouse spleen cells stimulated with phorbol myristate acetate and ionomycin. Selective depletion of spleen cell subsets by antibody and complement treatments established that granule exocytosis was mediated by NK cells. Blocking the cellular uptake of adenosine with NBTI or dilazep failed to prevent the inhibitory effect of adenosine, indicating the involvement of a cell-surface receptor. However, adenosine-induced inhibition of granule exocytosis was not blocked by the nonselective A₁ and A₂ receptor antagonists theophylline and 8-phenyltheophylline, the A₁ receptor antagonist DPCPX, or the A₂ receptor antagonist DMPX. In addition, the A₃ receptor agonists APNEA and NECA failed to affect granule exocytosis. Taken together, these data provide evidence that adenosine inhibits NK cell granule exocytosis by interacting with a novel extracellular receptor. A similar inhibitory effect of tumor-elaborated adenosine on the function of NK cells and other cytotoxic lymphocytes may contribute to tumor survival in the face of host cell-mediated immune defenses.